Mouse leukemia viruses (MLVs) are gammaretroviruses linked to induction of neoplasms and to neurological and immunodeficiency diseases. Inbred strains of laboratory mice and wild mouse species differ in their susceptibility to mouse gammaretrovirus infection and to virus-induced diseases, and they also differ in the types of MLVs that they carry. Susceptibility differences are due to variations in specific host genes, and we have been engaged in an ongoing effort to identify and characterize host genes that are either involved in virus resistance or that contribute to the disease process. There are two types of host genes involved in virus-induced disease. First, the mouse genome contains copies of mouse gammaretrovirus genomes, many of which can produce infectious and pathogenic viruses. Second, there are also host factors that interfere directly with virus infection and replication, and we are particularly interested in those factors that inhibit virus entry and the early post-entry stages of the virus replicative cycle. At the level of entry, resistance can be caused by polymorphisms in the cell surface receptors. After the gammaretrovirus enters the receptive cell, reverse transcription and translocation to the nucleus can be inhibited or altered by virus resistance factors Fv1, mApobec3, and TRIM5alpha. Our current aim is to characterize these active endogenous retroviruses and the host encoded resistance factors and their viral targets. The ultimate goal is to define the origin and extent of antiviral activity in Mus evolution, and elucidate the responsible mechanisms. This work relies heavily on wild mice because laboratory strains provide only a limited sampling of the genetic diversity in Mus. Also, wild mouse species allow us to examine survival strategies in natural populations that harbor virus and to follow the evolution of the resistance genes. These mice additionally provide a source of novel resistance genes and virus variants. One set of projects aims to identify viral and cell receptor determinants responsible for virus binding and entry. We are currently working on the XPR1 receptor for the xenotropic/polytropic MLVs (XP-MLVs). We have determined that, in mouse populations exposed to infectious virus, virus resistance is mediated by polymorphisms of the cell surface receptor. We have identified a total of six XPR1 susceptibility variants in wild mice and described the geographic and species distribution of these Mus Xpr1 variants. Five of these receptors restrict entry by two or more of the virus host range variants that rely on XPR1, and all of these receptors evolved in populations exposed to X-MLVs. Virtually all mammalian species have a functional XPR1 receptor and can be infected by X-MLVs. In our most recent study on X/P-MLV entry, we shifted our attention from restrictive receptors to the permissive XPR1 receptors that mediate entry of all X/P-MLVs. Most Mus species and some laboratory strains carry the permissive Xpr1-sxv allele, and there are other XPR1 receptors in various non-rodent mammalian species that are fully permissive despite considerable sequence variation in the receptor-determining regions. We examined permissive cells from four mammalian species (Mus dunni, human, mink, rabbit) in virus interference assays to determine if 9 different X/P-MLV isolates use the same of different receptor determinants in these 4 polymorphic, but fully permissive receptors. Results showed that some viruses produce distinctive species-specific interference profiles that can, in some cases, be correlated with specific receptor sequence variations. This suggests these MLV variants evolved to adapt to host receptor polymorphisms, to circumvent blocks by competing viruses or to avoid host-encoded envelope glycoproteins acquired for defense. In another series of experiments, we used phylogenetic and molecular biological methods to describe the sequence diversity and origins of infectious X/P-MLVs isolated from wild mice. These MLVs all derive from endogenous retroviruses (ERVs) that were acquired by the wild mouse progenitors of laboratory mice about 1 million years ago. Analysis of ten MLVs from Eurasian and American wild mice indicated that all of these viruses are intersubtype recombinants. Most of these MLVs are related to a distinctive, largely Y-chromosome-linked MLV ERV subtype. Examination of the viral envelope further identifies 3 subtypes of ecotropic MLVs due to duplications of different sizes and locations. This analysis helps define the relationships and origins of these viruses and emphasizes the importance of recombination in their evolution.